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Review
. 2005 Jun;5(6):545-53.
doi: 10.2174/1389557054023242.

Allosteric modulation of the adenosine family of receptors

Zhan-Guo Gao  1 , Soo-Kyung Kim, Adriaan P Ijzerman, Kenneth A Jacobson
Affiliations
Review

Allosteric modulation of the adenosine family of receptors

Zhan-Guo Gao et al. Mini Rev Med Chem. 2005 Jun.

Abstract

Allosteric modulators for adenosine receptors (ARs) are of an increasing interest and may have potential therapeutic advantage over orthosteric ligands. Benzoylthiophene derivatives (including PD 81,723), 2-aminothiazolium salts, and related allosteric modulators of the A(1) AR have been studied. The benzoylthiophene derivatives were demonstrated to be selective enhancers for the A(1) AR, with little or no effect on other subtypes of ARs. Allosteric modulation of the A(2A) AR has also been reported. A(3) allosteric enhancers may be predicted to be useful against ischemic conditions. We have recently characterized two classes of A(3) AR allosteric modulators: 3-(2-pyridinyl)isoquinolines (e.g. VUF5455) and 1H-imidazo-[4,5-c]quinolin-4-amines (e.g. DU124183), which selectively decreased the agonist dissociation rate at the human A(3)AR but not at A(1) and A(2A) ARs. DU124183 left-shifted the agonist conc.-response curve for inhibition of forskolin-stimulated cAMP accumulation in intact cells expressing the human A(3)AR with up to 30% potentiation of the maximal efficacy. The increased potency of A(3) agonists was evident only in the presence of an A(3) antagonist, since VUF5455 and DU124183 also antagonized, i.e. displaced binding at the orthosteric site, with K(i) values of 1.68 and 0.82 microM, respectively. A(3)AR mutagenesis studies implicated F182(5.43) and N274(7.45) in the action of the enhancers and was interpreted using a rhodopsin-based A(3)AR molecular model, suggesting multiple binding modes. Amiloride analogues, SCH-202676 (N-(2,3-diphenyl-1,2,4-thiadiazol-5(2H)-ylidene)methanamine), and sodium ions were demonstrated to be common allosteric modulators for at least three subtypes (A(1), A(2A), and A(3)) of ARs.

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Figures

Fig. 1
Fig. 1
Benzoylthiophenes as A1AR allosteric modulators.
Fig. 2
Fig. 2
Extension of the tetrahydrobenzo moiety of analogues of PD 81,723 1 with methylene groups.
Fig. 3
Fig. 3
Representative A1AR allosteric modulators from a series of recent patents [–16].
Fig. 4
Fig. 4
2-A minothiazolium salts as A1AR allosteric modulators.
Fig. 5
Fig. 5
A miloride derivatives and other allosteric modulators of A1 and A2A ARs.
Fig. 6
Fig. 6
The putative binding site of the A3AR with Cl-IB-MECA as an A3-selective agonist represented by atom type color with ball and stick model and VUF5455 37 as an allosteric modulator in dark shading with capped sticks. The side chains of amino acids in the binding site were shown in line model. The backbone of A3AR was displayed by tube. The amino acids in the putative allosteric binding site were S155, H158, Q167, S170 in EL2, L246, I249, N250, I253 in TM6, V259, P260 in EL3, and V263, L264 in TM7.
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